Process for the preparation of derivatives of 1-(2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R represents one or more groups independently selected from fluorine, chlorine, bromine, and iodine, said process comprising the cyclopropanation of a compound of formula (II) with ethylene carbonate or ethylene sulfate: wherein X is chlorine, bromine, iodine or a triflate group (CF 3 SO 3 ) or a group wherein R is as defined above and G is —CN or —COOR 2 wherein R 2 is a C 1 -C 4 straight or branched alkyl chain.

The invention claimed is: 
     
       1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R represents one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, and iodine,
 said process comprising: 
 (i) reacting a compound of formula (II): 
 
       
         
           
           
               
               
           
         
         wherein X is chlorine, bromine, iodine or a triflate group (CF 3 SO 3 ) or a group 
       
       
         
           
           
               
               
           
         
       
       wherein R is as defined above, and G is —CN or —COOR 2 , wherein R 2  is a C 1 -C 4  straight or branched alkyl chain,
 with a compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein Y is CO or SO 2  in the presence of a base,
 with the provisos that: 
 (a) when Y is CO, then said reacting is carried out at a temperature of 120° C. to 180° C. and the molar ratio of said compound of formula (II) to said compound of formula (III) is 1:10 to 1:30 and said reacting is carried out in the presence of a compound able to complex an alkaline metal cation, said compound being selected from the group consisting of a polyethylene glycol, a phosphonium salt, and a crown ether; and 
 (b) when G is —COOR 2 , then Y is SO 2 ; 
 to obtain a compound of formula (IV): 
 
       
         
           
           
               
               
           
         
         wherein X and G are as defined above; 
         (ii) when X is chlorine, bromine, iodine or a triflate group (CF 3 SO 3 ), coupling said compound of formula (IV) with a compound of formula (V): 
       
       
         
           
           
               
               
           
         
         wherein R is as defined above, 
         to obtain a compound of formula (IV) wherein X is 
       
       
         
           
           
               
               
           
         
         (iii) hydrolyzing said compound of formula (IV) wherein X is 
       
       
         
           
           
               
               
           
         
       
       obtained in (i) or (ii), to obtain said compound of formula (I); and
 (iv) optionally transforming said compound of formula (I) into a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A process according to  claim 1 , wherein G is —CN or —COOEt. 
     
     
       3. A process according to  claim 1 , wherein, in said compound of formula (II), X is bromine. 
     
     
       4. A process according to  claim 1 , wherein, in said compound of formula (II), X is 
       
         
           
           
               
               
           
         
       
     
     
       5. A process according to  claim 1 , wherein said compound of formula (I) is 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid of 
       
         
           
           
               
               
           
         
       
     
     
       6. A process according to  claim 1 , wherein, in (i), said base is selected from the group consisting of sodium tertbutylate, potassium tertbutylate, lithium tertbutylate, potassium carbonate, sodium hydride, lithium bis(trimethylsilyl)amide (LiHMDS); and lithium diisopropylamide (LDA). 
     
     
       7. A process according to  claim 1 , wherein Y is CO. 
     
     
       8. A process according to  claim 7 , wherein, in (i), the reaction is carried out at a temperature of 130° C. to 160° C. 
     
     
       9. A process according to  claim 7 , wherein, in (i), the molar ratio of said compound of formula (II) to said compound of formula (III) is 1:20 to 1:30. 
     
     
       10. A process according to  claim 8 , wherein, in (i), the molar ratio of said compound of formula (II) to said compound of formula (III) is 1:20 to 1:30. 
     
     
       11. A process according to  claim 1 , wherein said compound able to complex an alkaline metal cation is selected from the group consisting of PEG-200 and PEG-6000. 
     
     
       12. A process according to  claim 1 , wherein said compound of formula (II) and said compound able to complex an alkaline metal cation are present in a molar ratio of 1:0.02 to 1:2. 
     
     
       13. A process according to  claim 1 , wherein Y is SO 2 . 
     
     
       14. A process according to  claim 13 , wherein, in (i), the reaction is carried out at a temperature of from −20° C. to reflux temperature. 
     
     
       15. A process according to  claim 13 , wherein, in (i) the molar ratio of said compound of formula (II) to said compound of formula (III) is from 1:1 to 1:1.2. 
     
     
       16. A process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X is chlorine, bromine, iodine or a triflate group (CF 3 SO 3 ) or a group 
       
       
         
           
           
               
               
           
         
       
       wherein R represents one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, and G is —CN or —COOR 2 , wherein R 2  is a C 1 -C 4  straight or branched alkyl chain
 said process comprising: 
 (i) reacting a compound of formula (II): 
 
       
         
           
           
               
               
           
         
         with a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein Y is CO or SO 2  in the presence of a base, 
         with the provisos that: 
         (a) when Y is CO, then said reacting is carried out at a temperature of 120° C. to 180° C. and the molar ratio of said compound of formula (II) to said compound of formula (III) is 1:10 to 1:30 and said reacting is carried out in the presence of a compound able to complex an alkaline metal cation, said compound being selected from the group consisting of a polyethylene glycol, a phosphonium salt, and a crown ether; and 
         (b) when G is —COOR 2 , then Y is SO 2 ; 
         to obtain said compound of formula (IV). 
       
     
     
       17. A process according to  claim 16 , wherein G is —CN or —COOEt. 
     
     
       18. A process according to  claim 16 , wherein, in said compound of formula (II), X is bromine. 
     
     
       19. A process according to  claim 16 , wherein, in said compound of formula (II), X is 
       
         
           
           
               
               
           
         
       
     
     
       20. A process according to  claim 16 , wherein, in (i), said base is selected from the group consisting of sodium tertbutylate, potassium tertbutylate, lithium tertbutylate, potassium carbonate, sodium hydride, lithium bis(trimethylsilyl)amide (LiHMDS); and lithium diisopropylamide (LDA).